Physician, Entrepreneur, Teacher, Researcher, Consultant

Dr. Dan Miulli

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rotransmitter change complementing one in the serum or both.¹⁶   b-Amyloid proteins were found by Joachim and colleagues ¹⁶ not only in brain lesions in AD patients but also in skin, blood vessels, and intestinal tract. These facts, coupled to the need for an inexpensive and nonintrusive screening test, led to the use of plasma as the testing source.
Aspartate, glutamate, glutamate dehydrogenase, and a-ketoglutarate plasma concentrations were significantly above normal in patients with moderate AD in this limited pilot study. Rigid exclusion standards were used to clearly differentiate AD patients from those without AD, and from those with other diseases and causes of dementia or neurohogic diseases. Because neither autopsy nor biopsy verification of AD was available, the diagnosis of AD must be considered probable. However, the accuracy with use of our criteria¹⁷ approaches 90%.¹⁸ Our strict selection criteria may severely limit the number of persons in the general population who can be screened. Future studies must take this limitation into account, and must also use persons with AD regardless of current or past illness, medications, or abnormal laboratory values and those in early stages of the disease. Such studies should attempt to use CSF if possible.

The cause of the global increase in glutamate in the plasma and, presumptively, the proportional increase in the brain of AD patients in this pilot study is not fully understood. There are possible mechanisms, however, that may not be restricted entirely to the CNS.

Glutamate neurotoxicity can cause the cellular lesions in AD. Glutamate can induce neurofibrillary tangles, amyloid plaques, loss of dendritic spines, and a reduction in neuronal RNA.¹⁹ The primary reason for an increase in glutamate and other metabolites in AD patients would be a failure in the glutamate uptake system. Such failure would lead to a prolonged and concentrated synaptic glutamate level resulting in neurotoxicity, as has recently been demonstrated in patients with chronic migraine.²⁰
The adenosine triphosphate, chloride-dependent, presynaptic, glutamate uptake system and the sodium-dependent, astrocytic glutamate uptake system may deteriorate either because of lower bioenergy levels or other reasons. The carrier protein can become degraded as the result of enzymes or glycosylation.²¹ It may become blocked by a viral particle, an environmental toxin, or an autoimmune reaction. Once a decrease in glutamate uptake occurs, the neuron becomes depleted of this critical amino acid. Then, there would be a stimulus to manufacture more glutamate by conversion of the citric acid cycle intermediates; namely, a-ketoglutarate. There would then be a need for additional glutamate dehydrogenase. Aspartate would also be increased because of its rapid interconversion with glutamate. The Figure depicts this and subsequent reasons for

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